VacA (vacuolating cytotoxin A) is a key virulence factor in Helicobacter pylori infection, contributing to chronic gastritis and gastric adenocarcinoma. It induces vacuolation, disrupts cellular functions, and modulates immune responses, aiding bacterial survival in the harsh gastric environment. Genetic diversity in the vacA gene, particularly alleles like s1 and m1, is associated with more severe clinical outcomes. Recent advances in structural biology, especially cryo-electron microscopy, have revealed VacA’s oligomeric structure and its ability to form anion-selective channels in host cell membranes, providing important insights into its cytotoxic mechanisms. Understanding VacA’s structure and function is essential for unraveling its role in immune evasion and cellular damage. These findings also pave the way for targeted therapeutic strategies, such as subunit vaccines designed to neutralize VacA’s immunosuppressive effects, potentially leading to more effective control of H. pylori infections.

Accumulating evidence suggests an association between Helicobacter pylori infection and liver diseases; however, it remains unclear whether H. pylori or its extracellular products directly influence hepatocellular carcinoma (HCC) biology. Here, we examined the effects of viable H. pylori, sterile H. pylori-conditioned supernatant (Hp-CS), and isolated H. pylori-derived outer membrane vesicles (Hp-OMVs) on HCC cells. H. pylori adhered to and invaded Huh7 and Hepa1-6 cells, increased Cyclin D1 expression, and enhanced the growth of tumors derived from bacteria-exposed Hepa1-6 cells in immunocompetent C57BL/6J mice. Hp-CS increased HCC cell metabolic activity, colony formation, migration, and invasion. Hp-OMVs were characterized by transmission electron microscopy and nanoparticle tracking analysis. Exposure to Hp-OMVs increased HCC cell metabolic activity, colony formation, cell-cycle progression, and tumor growth in a syngeneic mouse model. Hp-OMVs also increased PI3K, AKT, and mTOR phosphorylation and elevated Cyclin D1 expression. The PI3K inhibitor LY294002 attenuated these molecular changes and reduced Hp-OMV-induced cell-cycle progression and colony formation. These findings show that H. pylori and its extracellular products promote proliferation-associated phenotypes in experimental HCC models. Hp-OMVs are biologically active extracellular components of H. pylori, and pharmacological inhibition supports the involvement of PI3K/AKT/mTOR signaling and Cyclin D1 upregulation in their growth-promoting effects.